Compositions Containing Fast-Leaching Plasticizers For Improved Performance Of Medical Devices

ABSTRACT

Medical implants containing a temporary plasticizer, methods of producing such implants, and methods of using the implants in treating a disease, or ameliorating one or more symptoms thereof, in a subject are provided.

CROSS REFERENCE TO RELATED APPLICATION

This is a divisional application of U.S. Ser. No. 11/796,454, which wasfiled on Apr. 27, 2007, which is a divisional of U.S. Ser. No.10/937,975, which was filed on Sep. 10, 2004, both applications areincorporated herein by reference.

BACKGROUND

1. Field of the Invention

This invention relates to a medical implant containing a temporaryplasticizer. More particularly, this invention relates to stentscontaining temporary plasticizers and their methods of use.

2. Description of the State of the Art

Many medical implants undergo a great deal of strain during theirmanufacture and use that can result in structural failure. Structuralfailure can occur as a result of manipulating the implant in preparationfor placing the implant in a subject and while placing the implant in adesired location in a subject. An example of such a medical implant is astent. Stents can be used to properly hold open and, if desired, expanda passageway within a subject. Typically, a stent may be compressed,inserted into a small vessel through a catheter, and then expanded to alarger diameter in a subject.

Stent placement can serve as an important step in a variety of medicalprocedures such as, for example, percutaneous transluminal coronaryangioplasty (PTCA)—a procedure used to treat heart disease. In PTCA, aballoon catheter is inserted through a brachial or femoral artery,positioned across a coronary artery occlusion, inflated to compressagainst atherosclerotic plaque to remodel the lumen of the coronaryartery, deflated and withdrawn from the patient. Problems with PTCAinclude formation of intimal flaps or torn arterial linings, both ofwhich can create another occlusion in the lumen of the coronary artery.Moreover, thrombosis and restenosis may occur several months after theprocedure and create a need for additional angioplasty or a surgicalby-pass operation. Stents are generally implanted after a PTCA to reduceocclusions, inhibit thrombosis and restenosis, and maintain patencywithin the lumen of the coronary artery. Examples of patents disclosingstents include U.S. Pat. Nos. 4,733,665, 4,800,882 and 4,886,062.

The manifestation of structural failure in a stent can be a formation ofcracks in high-strain areas of the stent such as, for example, in thecurved and intersecting regions that are extended during radialexpansion of the stent from a compressed form during placement of astent. As a result, structural failure can occur during placement of thestent in a subject and thereby affect stent performance. Accordingly,manufacturers of medical implants would benefit from new materials thatcan be highly strained in critical regions of the implant such as, forexample, in the loop regions of a stent. These new materials can be usedto form implants that can be highly strained during placement in asubject without structural failure and then become sufficiently rigidafter placement such that the complications arising from structuralimplant failure become a thing of the past.

SUMMARY

Medical implants comprising a temporary plasticizer, and their methodsof use, are provided. In one embodiment, the invention provides amedical article, wherein the medical article comprises an implant thatincludes a polymeric material. The polymeric material comprises aplasticizing agent capable of sufficiently increasing astrain-to-failure in the polymeric material to prevent or reduce aformation of cracks in the polymeric material while placing the implantin a subject. The plasticizing agent leaches from the polymeric materialafter placing the implant in a subject to provide a sufficient rigidityin the polymeric material, and the leaching occurs in less than anamount of time necessary for a required dimension of the implant tochange substantially in response to a stress.

In another embodiment, a method of treating a disease in a subject, orameliorating one or more symptoms thereof is provided. The methodincludes placing an implant that includes a polymeric material in asubject, wherein the polymeric material comprises a plasticizing agentcapable of sufficiently increasing a strain-to-failure in the polymericmaterial to prevent a formation of cracks in the polymeric materialwhile placing the implant in a subject. The plasticizing agent leachesfrom the polymeric material after placing the implant in the subject toprovide a sufficient rigidity in the polymeric material, and theleaching occurs in less than an amount of time necessary for a requireddimension of the implant to change substantially in response to astress.

In another embodiment, a method of producing a medical articlecomprising a temporary plasticizing agent is provided. The methodcomprises combining a polymer with a plasticizing agent capable ofsufficiently increasing a strain-to-failure in the polymeric material toprevent or reduce a formation of cracks in the polymeric material whileplacing an implant in a subject. The plasticizing agent leaches from thepolymeric material after placing the implant in the subject to provide asufficient rigidity in the polymeric material, and the leaching occursin less than an amount of time necessary for a required dimension of theimplant to change substantially in response to a stress.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 a-1 c illustrate a method for delivering a stent according toembodiments of the present invention.

FIG. 2 illustrates a portion of a stent structure to show variations instrain regions according to embodiments of the present invention.

FIGS. 3 a-3 c illustrate the nonuniformity of stress and strain incurved struts of a stent.

FIGS. 4 a and 4 b illustrate the nonuniformity of stress and strain inintersecting struts of a stent.

DETAILED DESCRIPTION

As discussed in more detail below, the invention generally includes amedical article comprising an implant and a method of using the medicalarticle in a subject to treat or ameliorate one or more symptoms of adisease. The term “subject” and “patient” can be used interchangeably inthe present invention and refer to an animal such as a mammal including,but not limited to, non-primates such as, for example, a cow, pig,horse, cat, dog, rat and mouse; and primates such as, for example, amonkey or a human.

The implant contains a temporary plasticizer that allows for a highlevel of strain during placement of the implant in the subject bypreventing or reducing a formation of cracks in the implant that wouldotherwise occur without the temporary plasticizer. The plasticizer istemporary in that it leaches from the implant in less than an amount oftime necessary for a required dimension of the implant to changesubstantially in response to a stress, thus leaving an implant in asubject that is sufficiently rigid for its intended purpose. A change ina required dimension is “substantial” when it has occurred to a degreethat significantly affects the clinical utility of a medical device oris more than what may be considered acceptable to one having ordinaryskill in the art. In a stent, for example, a required dimension is thediameter of the stent, and a reduction in the diameter of the stent issubstantial when it significantly affects the ability of the stent tophysically hold open, or expand, the lumen of an organ in a subject.Alternatively, the reduction in the diameter of the stent is“substantial” when the reduction is more than the acceptable standard inthe art or the stent is no longer considered as being effective for theprocedure for which it was used.

In some embodiments, a change in a required dimension is substantialwhen the change occurs in an amount ranging from about 0.01% to about50%, from about 0.1% to about 40%, from about 0.2% to about 30%, fromabout 0.3% to about 25%, from about 0.5% to about 20%, from about 1% toabout 10%, or any range therein. In some embodiments, the implantcomprises a stent or a vena cava filter, and the required dimension is adiameter of the stent or vena cava filter following deployment of thestent or vena cava filter in a subject. In these embodiments, the changein the required dimension is a reduction in the diameter of the stent orvena cava filter ranging from about 0.1% to about 20%, from about 1% toabout 20%, from about 3% to about 20%, from about 5% to about 20%, fromabout 0.5% to about 15%, from about 1% to about 10%, or any rangetherein.

The medical articles provided by the present invention provide a methodof treating a disease in a subject, or ameliorating one or more symptomsthereof that are associated with the disease. The term “treating” refersto the placement of a medical implant that contains one or morediagnostic, therapeutic or prophylactic agents.

FIGS. 1 a-1 c illustrate a method for delivering a stent according toembodiments of the present invention. In FIG. 1 a, a medical assemblyhaving a catheter body 101, a balloon 102, and a stent 103 having loopregions 104 is positioned in a vascular organ 105. The vascular organ105 has a lumen that is constricted by the presence of a vascular lesion106. In FIG. 1 b, the balloon 102 is inflated to compress against thevascular lesion 106 to remodel the vascular organ 105 and increase thediameter of the lumen of vascular organ 105. Concurrently, loop regions104 are subject to a high level of strain during the inflation ofballoon 102. As the balloon 102 is inflated, the stent 103 is subject tostress and strain in its expansion and release from the balloon 102. InFIG. 1 c, the balloon 102 has been deflated and withdrawn from thevascular organ 105 to complete delivery of the stent 103 in the regionof the vascular lesion 106, wherein the stent 103 acts as a rigidstructure to properly hold open and, if desired, expand the lumen ofvascular organ 105.

FIG. 2 illustrates a portion of a stent structure to show variations instrain regions according to embodiments of the present invention. InFIG. 2, a design and configuration of a stent 201 is provided forexample only and is in no way intended to limit the scope of the presentinvention. Stent 201 may include a number of interconnecting elements orstruts 202, the geometry or shape of which may vary throughout such astent. General types of struts 202 can include straight struts 203,curved struts 204, and intersecting struts 205. Each of these struts areisolated regions that are subject to stress upon compression andexpansion of the stent 201 during, for example, either manufacture orplacement of the stent 201 in a subject. The design and configuration ofthe stent 201 allows for a radial compression during manufacture and aradial expansion during placement, but radial rigidity is also desiredfor withstanding the stresses associated with holding a body lumen open.

The stress and strain experienced by a medical implant duringmanufacture and placement in a subject is not uniform throughout theimplant such as, for example, during radial compression and expansion.There can be a nonuniformity of stress and strain that can occur duringany manipulation of the stent such as, for example, during compressionof the stent onto a balloon catheter in preparation for delivery orduring expansion of the stent by the balloon catheter during delivery ofthe stent into an organ. Some portions of a stent pattern may experiencelittle to no strain, whereas others may have a relatively high level ofstrain. For example, the straight struts 203 experience little to nostrain during radial compression and expansion, whereas curved struts204 and intersecting struts 205 experience relatively high-strain duringradial compression and expansion.

FIGS. 3 a-3 c illustrate the nonuniformity of stress and strain incurved struts of a stent. FIG. 3 a illustrates a curved strut 301 in thestent 201 in an unexpanded state that includes straight sections 302 andcurved sections 303 with an angle θ₁ 304. Radial expansion of the stent201 results in an increase of angle θ₁ 304 between straight sections 302to angle θ₂ 305, as shown in FIG. 3 b. FIGS. 3 a and 3 b illustrate thecurved strut 301 in a plane of bending, which causes little to no strainin straight sections 302 and relatively high levels of stress and strainin most of curved section 303. During radial expansion of the stent, aconcave portion 306 of the curved section 303 experiences relativelyhigh tensile stress and strain and a convex portion 307 of the curvedsection 303 experiences relatively high compressive strain. FIG. 3 cillustrates an expanded view of the curve in the curved section 303 andindicates a neutral axis 308 having little to no strain and beingpositioned along a center of a latitudinal width 309 of the curvedsection 303.

FIGS. 4 a and 4 b illustrate the nonuniformity of stress and strain inintersecting struts of a stent. FIG. 4 a illustrates an intersectingstrut 401 in the stent 201 in an unexpanded state that includes straightsections 402 and intersection 403 with an angle θ₁ 404. Radial expansionof stent 201 results in an increase of angle θ₁ 404 between straightsections 402 to angle θ₂ 405, as shown in FIG. 4 b. FIGS. 4 a and 4 billustrate an intersecting strut 401 in a plane of bending, which causeslittle to no strain in the straight sections 402 and relatively highlevels of stress and strain in most of the intersections 403. Duringradial expansion, a first concave portion 406 of the curved section 403experiences relatively high tensile stress and strain and a secondconcave portion 407 of the curved section 403 experiences relativelyhigh compressive strain.

It is to be appreciated that the descriptions and analyses of the stressand strain provided herein are not intended to be limiting. Suchdescriptions and analyses are merely provided to illustrate generalconcepts and methodology of the invention as it may apply to particularembodiments such as, for example, some stent applications.

Structural failure of a stent can be manifested in a formation of cracksin high-strain areas of the stent such as, for example, in the curvedsection 303 and the intersections 403 that are extended during radialexpansion from a compressed form during placement of the stent 201 in asubject. As a result, structural failure can occur during placement ofthe stent 201 in a subject and, accordingly, affects stent performance.

In some embodiments, a medical implant comprising a polymeric materialand a plasticizing agent that is capable of sufficiently increasing astrain-to-failure in the polymeric material. The term“strain-to-failure” refers to the total strain that can be experiencedby a polymeric material before the structure of the polymeric materialfails such that it is no longer capable of performing its intendedfunction, or the failure is a result of a damage that is greater than anacceptable standard known to one of skill in the art. For example, thestrain-to-failure of a stent can be the amount of strain that a stentcan experience prior to failure in a high-strain region of the stent.

In some embodiments, the strain-to-failure can be measured in alaboratory, for example, using a tensile test. A “tensile test” is ameasure of the force required to break a specimen of a material and istypically used to produce a stress-strain relationship that can be usedto determine the tensile modulus of a material. However, the measure canalso identify the point at which the material will fail when subject tostrain. Since the physical properties of a material can vary withtemperature, a material should be tested at the temperature of theenvironment in which it will be stressed. In other embodiments, thestrain-to-failure can be determined using an empirical approach such asa finite element analysis (FEA), which can be used to calculate themaximum strain in high-strain regions of polymers.

In some embodiments, the medical implant is a stent, and thestrain-to-failure of the stent is the amount of strain that can beexperienced by the stent before the stent can no longer properly holdopen and, if desired, expand a passageway within a subject. In otherembodiments, the stent fails due to cracks and/or breaks in thehigh-strain regions of the stent. In these embodiments, the plasticizingagent can, inter alia, prevent a formation of cracks in the polymericmaterial that otherwise may occur while placing the implant in asubject, wherein the plasticizing agent leaches from the polymericmaterial after placing the implant in the subject to provide an implantthat is sufficiently rigid to perform its intended function. In otherembodiments, the plasticizer leaches from the implant in less than anamount of time necessary for a required dimension of the implant tochange substantially in response to a stress such as, for example, thestress placed on a stent by the walls of a lumen that is being held openand/or expanded by the stent.

Placement of an implant in a subject can require a manipulation of theimplant to an extent that may result in failure of the implant due tothe strain of the manipulation. In some embodiments, the implantcomprises a component that can be expanded mechanically. In theseembodiments, some components can be expanded with a balloon such as, forexample, the expansion of a stent with a balloon catheter. In otherembodiments, some components can self-expand while placing the implantin a subject, wherein the self-expansion may occur, for example, as astent or vena cava filter is forced out of a delivery device (e.g., acatheter) and into a lumen of a subject.

A stent can be used to treat a disease within a subject and can resemblea tube-like body that may be used to open a lumen within an organ in thesubject, maintain lumen patency, or reduce the likelihood that the lumenwill narrow again. Diseases can be present in a variety of organs withina patient. Examples of such organs include, but are not limited to,vascular organs such as, for example, coronary arteries and hepaticveins; renal organs such as, for example, urethras and ureters; biliaryorgans such as, for example, biliary ducts; pulmonary organs such as,for example, tracheas, bronchi and bronchioles; and gastrointestinalorgans such as, for example, esophagi and colons, to name a few. Stentscan be used to treat and/or ameliorate one or more symptoms of a varietyof diseases that include, but are not limited to, atherosclerosis,benign prostatic hypertrophy, recoiling lesions after percutaneoustransluminal angioplasty and in dissections, chronic occlusions,anastomotic hyperplasia in vein grafts and synthetic vascular grafts,vulnerable plaque, aneurysms of the aorta and large arteries,arteriovenous fistulae and traumatic leaks, malignant stenosis of thegastrointestinal tract, acute ileus in colorectal cancer, biliaryclosure from cholangiocarcinoma or other hepatic cancers, benigncompression of the trachea and malignant tracheobronchial obstructions.

A stent can be composed of any materials and have any dimensions knownto be useful to one of skill in the art. In some embodiments, the stentsinclude, but are not limited to, tubular stents, self-expanding stents,coil stents, ring stents, multi-design stents, and the like. In otherembodiments, the stents are metallic; low-ferromagnetic;non-ferromagnetic; biostable polymeric; biodegradable polymeric orbiodegradable metallic. In some embodiments, the stents are coated suchas, for example, with a polymer containing a drug. A coating can beexclusively on the outer surface, exclusively on the inner surface, oron both the outer surface and the inner surface of the stent.

A stent can be composed of a metal, an alloy, a polymer, or acombination thereof. Examples of materials used to form stents include,but are not limited to, ELASTINITE® (Guidant Corp.), NITINOL (NitinolDevices and Components), stainless steel, tantalum, tantalum-basedalloys, nickel-titanium alloy, platinum, platinum-based alloys such as,for example, platinum-iridium alloys, iridium, gold, magnesium,titanium, titanium-based alloys, zirconium-based alloys, alloyscomprising cobalt and chromium (ELGILOY®, Elgiloy Specialty Metals,Inc.; MP35N and MP20N, SPS Technologies), and combinations thereof. Thetradenames “MP35N” and “MP20N” describe alloys of cobalt, nickel,chromium and molybdenum. The MP35N consists of 35% cobalt, 35% nickel,20% chromium, and 10% molybdenum. The MP20N consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum.

Since stents can be placed in a variety of organs within a subject,stents can have a variety of dimensions. In some embodiments, thediameter of the stent can range from about 0.025 mm to about 50 mm, fromabout 0.05 mm to about 25 mm, from about 0.1 mm to about 20 mm, fromabout 0.25 mm to about 15 mm, from about 0.50 mm to about 10 mm, fromabout 1.0 mm to about 5 mm, or any range therein. In other embodiments,the diameter of the stent can range from about 0.05 mm to about 2.5 mm,from about 0.10 mm to about 2.0 mm, from about 0.25 mm to about 1.5 mm,from about 0.50 mm to about 1.0 mm, or any range therein. In otherembodiments, the diameter of the stent can range from about 10 mm toabout 25 mm, from about 12 mm to about 22 mm, from about 15 mm to about20 mm, or any range therein. In some embodiments, the length of thestent can range from about 0.1 mm to about 100 mm, from about 0.5 mm toabout 75 mm, from about 1.0 mm to about 60 mm, from about 2.0 mm toabout 60 mm, from about 4.0 mm to about 60 mm, from about 1.0 mm toabout 50 mm, from about 5.0 mm to about 50 mm, from about 1.5 mm toabout 40 mm, from about 2.0 mm to about 30 mm, or any range therein.

The medical articles of the present invention can be formed usingbioabsorbable polymers, biostable polymers or a combination thereof. Forthe purposes of the present invention, a polymer or coating is“bioabsorbable” or “biodegradable” when it is capable of beingcompletely or substantially degraded or eroded when exposed to either anin vivo environment or an in vitro environment having physical,chemical, or biological characteristics substantially similar to thoseof the in vivo environment within a subject. A polymer or coating is“degradable or erodable” when it can be gradually broken-down, resorbed,absorbed and eliminated by, for example, hydrolysis, enzymolysis,metabolic processes, bulk or surface erosion, and the like within asubject. It should be appreciated that traces or residue of polymer mayremain following biodegradation. The terms “bioabsorbable,”“biodegradable,” and “bioerodable” are used interchangeably in thisapplication. A “biostable” polymer is a polymer that is notbioabsorbable.

The polymers used in the present invention can be hydrophobic,hydrophilic, amphiphilic, biodegradable, or a combination thereof.Examples of hydrophobic polymers include, but are not limited to,poly(ester amide), polystyrene-polyisobutylene-polystyrene blockcopolymer (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL),poly(L-lactide), poly(D,L-lactide), polylactic acid (PLA),poly(lactide-co-glycolide), poly(glycolide), polyalkylene,polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(4-hydroxyhexanoate), mid-chain polyhydroxyalkanoate, poly(trimethylene carbonate), poly(orthoester), polyphosphazenes,poly(phosphoester), poly(tyrosine derived arylates), poly(tyrosinederived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride(PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane,poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP),poly(vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE),poly(butyl methacrylate), poly(methyl methacrylate),poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinylacetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes),poly(ether-urethanes), poly(carbonate-urethanes),poly(silicone-urethanes), poly(2-hydroxyethyl methacrylate), Solef® PVDF(polyvinylidene fluoride), poly(urea-urethanes), and combinationsthereof.

Examples of hydrophilic polymers include, but are not limited to,polymers and co-polymers of carboxyl and hydroxyl bearing monomersincluding, but not limited to, hydroxylethyl methacrylate (HEMA),hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide,alkoxymethacrylate, alkoxyacrylate, and 3-trimethylsilylpropylmethacrylate (TMSPMA), poly(methyl methacrylate) (PMMA), poly(ethyleneglycol) (PEG), polypropylene glycol) (PPG), PEG acrylate (PEGA), PEGmethacrylate, methacrylic acid (MA), ethylene-vinyl acetate, acrylicacid (AA), SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG,PLA-PEG, PMMA-PEG, PDMS-PEG, PVDF-PEG, PLURONIC™ surfactants(polypropylene oxide-co-polyethylene glycol), poly(tetramethyleneglycol), phosphorylcholine, 2-methacryloyloxyethyl phosphorylcholine(MPC), n-vinyl pyrrolidone (VP), hydroxy functional poly(vinylpyrrolidone), polyalkylene oxide, dextran, dextrin, sodium hyaluronate,hyaluronic acid, heparin, elastin, chitosan, and combinations thereof.

Examples of biodegradable polymers include, but are not limited to,polymers having repeating units such as, for example, anα-hydroxycarboxylic acid, a cyclic diester of an α-hydroxycarboxylicacid, a dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, anepoxide, a glycol, an anhydride, a lactic acid, a glycolic acid, alactide, a glycolide, an ethylene oxide, an ethylene glycol, orcombinations thereof. In some embodiments, the biodegradable polymersinclude, but are not limited to, polyesters, polyhydroxyalkanoates(PHAs), poly(ester amides); amino acids; PEG and/or alcohol groups,polycaprolactones, poly(L-lactide), poly(D,L-lactide),poly(D,L-lactide-co-PEG) block copolymers,poly(D,L-lactide-co-trimethylene carbonate), polyglycolides,poly(lactide-co-glycolide), polydioxanones, polyorthoesters,polyanhydrides, poly(glycolic acid-co-trimethylene carbonate),polyphosphoesters, polyphosphoester urethanes, poly(amino acids),polycyanoacrylates, poly(trimethylene carbonate), poly(imino carbonate),polycarbonates, polyurethanes, copoly(ether-esters) (e.g., PEO/PLA),polyalkylene oxalates, polyphosphazenes, PHA-PEG, and any derivatives,analogs, homologues, salts, copolymers and combinations thereof.

In other embodiments, the biodegradable polymers may include, but arenot limited to, PHAs such as, for example, poly(α-hydroxyacids);poly(β-hydroxyacids) such as poly(3-hydroxybutyrate) (PHB);poly(3-hydroxybutyrate-co-valerate) (PHBV); poly(3-hydroxypropionate)(PHP); poly(3-hydroxyhexanoate) (PHH); a poly(4-hydroxyacid) such aspoly(4-hydroxybutyrate), poly(4-hydroxyvalerate), orpoly(4-hydroxyhexanoate); poly(hydroxyvalerate); and any derivatives,analogs, homologues, salts, copolymers and combinations thereof. Inother embodiments, the biodegradable polymers include, but are notlimited to, polyanhydrides, poly(hydroxyethyl methacylate),poly(N-acylhydroxyproline)esters, poly(N-palmitoylhydroxyproline)esters, polyphosphazenes, poly(tyrosine carbonates),poly(tyrosine arylates), and any derivatives, analogs, homologues,salts, copolymers and combinations thereof.

It should also be appreciated that, in some embodiments, one of skill inthe art may select one or more particular polymers in order to excludeany one or any combination of the above-described polymers.

Agents

The medical articles of the present invention can comprise an agent. Inone embodiment, the agent can be included in the body of a medicalarticle such as, for example, a biodegradable polymeric stent. Inanother embodiment, the agent can be included in a coating for a medicalarticle. An “agent” is a moiety that may be biobeneficial, bioactive,diagnostic, plasticizing, or a combination thereof. A “moiety” includes,but is not limited to, functional groups composed of at least 1 atom,bonded residues in a macromolecule, individual units in a copolymer andentire polymeric blocks.

Bioactive and Biobeneficial Agents

A “bioactive agent” is a moiety that is mixed, blended, bonded or linkedto a polymer coating, or to a polymer from which a stent is made, andprovides a therapeutic effect, a prophylactic effect, both a therapeuticand a prophylactic effect, or other biologically active effect uponrelease from the stent. The bioactive agents of the present inventionmay remain linked to a portion of the polymer or be released from thepolymer. A “biobeneficial agent” is an agent that can be mixed, blended,bonded or linked to a polymer that provides a biological benefit withina subject without necessarily being released from the stent. The terms“plasticizer” and “plasticizing agent” are described in more detailbelow and include any agent that can be added to a polymeric compositionto modify its mechanical properties or the mechanical properties of aproduct formed from the polymeric composition.

A “diagnostic agent” can be a type of bioactive or biobeneficial agentthat can be used, for example, in diagnosing the presence, nature,and/or extent of a disease or medical condition in a subject. In oneembodiment, a diagnostic agent can be any agent which may be used inconnection with methods for imaging an internal region of a patientand/or diagnosing the presence or absence of a disease in a patient.Diagnostic agents include, for example, contrast agents for use inconnection with ultrasound imaging, magnetic resonance imaging (MRI),nuclear magnetic resonance (NMR), computed tomography (CT), electronspin resonance (ESR), nuclear medical imaging, optical imaging,elastography, radiofrequency (RF) and microwave laser. Diagnostic agentsmay also include any other agents useful in facilitating diagnosis of adisease or other condition in a patient, whether or not imagingmethodology is employed.

Biobeneficial agents are moieties that may be mixed, blended, bonded orlinked to a polymer and are capable of providing a biological benefitsuch as, for example, control of protein adsorption on an implantsurface, without being released from the polymer. Biobeneficial agentscan have a reactive group that can be used to link the agent to apolymer. Examples of reactive groups include, but are not limited to,hydroxyl, carboxyl, and amino groups. In some embodiments, the molecularweight of the agent should be at or below about 40,000 Daltons, or anyrange therein, to ensure elimination of the agent from a subject. In oneembodiment, the molecular weight of the agent ranges from about 300Daltons to about 40,000 Daltons, from about 8,000 Daltons to about30,000 Daltons, from about 10,000 Daltons to about 20,000 Daltons, orany range therein.

Examples of biobeneficial agents include, but are not limited to,poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamidemethyl propane sulfonic acid), poly(styrene sulfonate), sulfonateddextran, polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate),hyaluronic acid, heparin and any derivatives, analogs, homologues,congeners, salts, copolymers and combinations thereof. It is to beappreciated that one skilled in the art should recognize that some ofthe groups, subgroups, and individual biobeneficial agents may not beused in some embodiments of the present invention.

The poly(alkylene glycols) include, but are not limited to, PEG, methoxypoly(ethylene glycol) (mPEG), poly(ethylene oxide), PPG,poly(tetramethylene glycol), poly(ethylene oxide-co-propylene oxide) andany derivatives, analogs, homologues, congeners, salts, copolymers andcombinations thereof. In one embodiment, the poly(alkylene glycol) ismPEG. In some embodiments, the PEGs can have molecular weights rangingfrom about 400 Daltons to about 30,000 Daltons, from about 400 Daltonsto about 25,000 Daltons, from about 400 Daltons to about 20,000 Daltons,from about 400 Daltons to about 15,000 Daltons, from about 500 Daltonsto about 10,000 Daltons, from about 750 Daltons to about 7500 Daltons,from about 1000 Daltons to about 10,000 Daltons, from about 1000 Daltonsto about 5000 Daltons, or any range therein.

The copolymers that may be used as biobeneficial agents include, but arenot limited to, any derivatives, analogs, homologues, congeners, salts,copolymers and combinations of the foregoing examples of biobeneficialagents. Examples of copolymers that may be used as biobeneficial agentsin the present invention include, but are not limited to, copolymers ofPEG and hyaluronic acid; copolymers of PEG and heparin; graft copolymersof poly(L-lysine) and PEG; and, any derivative, analog, congener, salt,or combination thereof, of the copolymers. In one embodiment, thecopolymer that may be used as a biobeneficial agent is a copolymer ofPEG and hyaluronic acid, or any derivative, analog, congener, salt,copolymer or combination thereof.

The bioactive agents can be any moiety capable of contributing to atherapeutic effect, a prophylactic effect, both a therapeutic andprophylactic effect, or other biologically active effect in a subject.The bioactive agents include, but are not limited to, small molecules,nucleotides, oligonucleotides, polynucleotides, nucleic acids, aminoacids, oligopeptides, polypeptides, and proteins. In one example, thebioactive agent inhibits the activity of vascular smooth muscle cells.In another example, the bioactive agent controls migration orproliferation of smooth muscle cells to inhibit restenosis.

Bioactive agents include, but are not limited to, antiproliferatives,antineoplastics, antimitotics, anti-inflammatories, antiplatelets,anticoagulants, antifibrins, antithrombins, antibiotics, antiallergics,antioxidants, and any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof. It is to beappreciated that one skilled in the art should recognize that some ofthe groups, subgroups, and individual bioactive agents may not be usedin some embodiments of the present invention.

Antiproliferatives include, for example, actinomycin D, actinomycin IV,actinomycin I₁, actinomycin X₁, actinomycin C₁, and dactinomycin(COSMEGEN®, Merck & Co., Inc.). Antineoplastics or antimitotics include,for example, paclitaxel (TAXOL®, Bristol-Myers Squibb Co.), docetaxel(TAXOTERE®, Aventis S.A.), docetaxel, methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride(ADRIAMYCIN®, Pfizer, Inc.) and mitomycin (MUTAMYCIN®, Bristol-MyersSquibb Co.), and any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof. Antiplatelets,anticoagulants, antifibrin, and antithrombins include, for example,sodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors (ANGIOMAX®, Biogen, Inc.), and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof. Cytostatic or antiproliferative agents include, for example,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.), cilazapril orlisinopril (PRINIVIL®, and PRINZIDE®, Merck & Co., Inc.); calciumchannel blockers such as nifedipine; colchicines; fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid); histamineantagonists; lovastatin (MEVACOR®, Merck & Co., Inc.); monoclonalantibodies including, but not limited to, antibodies specific forPlatelet-Derived Growth Factor (PDGF) receptors; nitroprusside;phosphodiesterase inhibitors; prostaglandin inhibitors; suramin;serotonin blockers; steroids; thioprotease inhibitors; PDGF antagonistsincluding, but not limited to, triazolopyrimidine; and nitric oxide, andany prodrugs, metabolites, analogs, homologues, congeners, derivatives,salts and combinations thereof. Antiallergic agents include, but are notlimited to, pemirolast potassium (ALAMAST®, Santen, Inc.), and anyprodrugs, metabolites, analogs, homologues, congeners, derivatives,salts and combinations thereof.

Other bioactive agents useful in the present invention include, but arenot limited to, free radical scavengers; nitric oxide donors; rapamycin;methyl rapamycin; everolimus; tacrolimus;40-O-(3-hydroxy)propyl-rapamycin;40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containingrapamycin analogs such as those described in U.S. Pat. No. 6,329,386;estradiol; clobetasol; idoxifene; tazarotene; alpha-interferon; hostcells including, but not limited to prokaryotes and eukaryotes such as,for example, epithelial cells and genetically engineered epithelialcells; dexamethasone; and, any prodrugs, metabolites, analogs,homologues, congeners, derivatives, salts and combinations thereof.

Free radical scavengers include, but are not limited to,2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical (TEMPO);4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical(4-amino-TEMPO); 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, freeradical (TEMPOL) 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methylsulfate, free radical; 16-doxyl-stearic acid, free radical; superoxidedismutase mimic (SODm) and any analogs, homologues, congeners,derivatives, salts and combinations thereof. Nitric oxide donorsinclude, but are not limited to, S-nitrosothiols, nitrites,N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazeniumdiolates such as spermine diazenium diolate, and any analogs,homologues, congeners, derivatives, salts and combinations thereof.

Examples of diagnostic agents include radiopaque materials and include,but are not limited to, materials comprising iodine oriodine-derivatives such as, for example, iohexyl and iopamidol, whichare detectable by x-rays. Other diagnostic agents such as, for example,radioisotopes, are detectable by tracing radioactive emissions. Otherdiagnostic agents may include those that are detectable by magneticresonance imaging (MRI), ultrasound and other imaging procedures suchas, for example, fluorescence and positron emission tomagraphy (PET).Examples of agents detectable by MRI are paramagnetic agents, whichinclude, but are not limited to, gadolinium chelated compounds. Examplesof agents detectable by ultrasound include, but are not limited to,perflexane. Examples of fluorescence agents include, but are not limitedto, indocyanine green. Examples of agents used in diagnostic PETinclude, but are not limited to, fluorodeoxyglucose, sodium fluoride,methionine, choline, deoxyglucose, butanol, raclopride, spiperone,bromospiperone, carfentanil, and flumazenil.

It should be appreciated that the agents of the present invention canhave both biobeneficial and bioactive properties, and thatclassification of an agent as a biobeneficial agent does not precludethe use of that agent as a bioactive agent. Likewise, classification ofan agent as a bioactive agent does not preclude the use of that agent asa biobeneficial agent. It should also be appreciated that, in someembodiments, one of skill in the art may select one or more particularagents in order to exclude any one or any combination of theabove-described agents.

Plasticizing Agents

The terms “plasticizer” and “plasticizing agent” can be usedinterchangeably in the present invention and can include any bioactive,biobeneficial or diagnostic agent described above. A plasticizing agentcan include any agent or combination of agents that can be added tomodify the mechanical properties of a polymeric composition or a productformed from the polymeric composition.

Without intending to be bound by any theory or mechanism of action,plasticizers can be added, for example, to reduce crystallinity, lowerthe glass-transition temperature (T_(g)), or reduce the intermolecularforces between polymers, with a design goal that may include creating orenhancing a flow between polymers in the composition. The mechanicalproperties that are modified include, but are not limited to, Young'smodulus, tensile strength, impact strength, tear strength, andstrain-to-failure. A plasticizer can be monomeric, polymeric,co-polymeric, or a combination thereof, and can be added to a polymericcomposition with or without covalent bonding. Plasticization andsolubility are analogous to the extent that selecting a plasticizerinvolves considerations similar to the considerations in selecting asolvent such as, for example, polarity. Furthermore, plasticizers canalso be added to a polymeric composition through covalent bonding thatchanges the molecular structure of the polymer through copolymerization.

Examples of plasticizing agents include, but are not limited to, lowmolecular weight polymers such as, for example, single-block polymers,multi-block polymers, and copolymers; oligomers such as, for example,lactic acid oligomers including, but not limited to, ethyl-terminatedoligomers of lactic acid; dimers of cyclic lactic acid and glycolicacid; small organic molecules; hydrogen bond forming organic compoundswith and without hydroxyl groups; polyols such as low molecular weightpolyols having aliphatic hydroxyls; alkanols such as butanols, pentanolsand hexanols; sugar alcohols and anhydrides of sugar alcohols;polyethers such as poly(alkylene glycols); esters such as citrates,phthalates, sebacates and adipates; polyesters; aliphatic acids;saturated and unsaturated fatty acids; fatty alcohols; cholesterol;steroids; phospholipids such as, for example, lecithin; proteins such asanimal proteins and vegetable proteins; oils such as, for example, thevegetable oils and animal oils; silicones; acetylated monoglycerides;diglycerides; triglycerides; amides; acetamides; sulfoxides; sulfones;pyrrolidones; oxa acids; diglycolic acids; and any analogs, derivatives,copolymers and combinations thereof.

In some embodiments, the plasticizers include, but are not limited toother polyols such as, for example, caprolactone diol, caprolactonetriol, sorbitol, erythritol, glucitol, mannitol, sorbitol, sucrose, andtrimethylol propane. In other embodiments, the plasticizers include, butare not limited to, glycols such as, for example, ethylene glycol,diethylene glycol, triethylene glycol, tetraethylene glycol, propyleneglycol, butylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, pentamethylene glycol, hexamethylene glycol;glycol-ethers such as, for example, monopropylene glycol monoisopropylether, propylene glycol monoethyl ether, ethylene glycol monoethylether, and diethylene glycol monoethyl ether; and any analogs,derivatives, copolymers and combinations thereof.

In other embodiments, the plasticizers include, but are not limited toesters such as glycol esters such as, for example, diethylene glycoldibenzoate, dipropylene glycol dibenzoate, triethylene glycolcaprate-caprylate; monostearates such as, for example, glycerolmonostearate; citrate esters; organic acid esters; aromatic carboxylicesters; aliphatic dicarboxylic esters; fatty acid esters such as, forexample, stearic, oleic, myristic, palmitic, and sebacic acid esters;triacetin; poly(esters) such as, for example, phthalate polyesters,adipate polyesters, glutate polyesters, phthalates such as, for example,dialkyl phthalates, dimethyl phthalate, diethyl phthalate, isopropylphthalate, dibutyl phthalate, dihexyl phthalate, dioctyl phthalate,diisononyl phthalate, and diisodecyl phthalate; sebacates such as, forexample, alkyl sebacates, dimethyl sebacate, dibutyl sebacate;hydroxyl-esters such as, for example, lactate, alkyl lactates, ethyllactate, butyl lactate, allyl glycolate, ethyl glycolate, and glycerolmonostearate; citrates such as, for example, alkyl acetyl citrates,triethyl acetyl citrate, tributyl acetyl citrate, trihexyl acetylcitrate, alkyl citrates, triethyl citrate, and tributyl citrate; estersof castor oil such as, for example, methyl ricinolate; aromaticcarboxylic esters such as, for example, trimellitic esters, benzoicesters, and terephthalic esters; aliphatic dicarboxylic esters such as,for example, dialkyl adipates, alkyl allylether diester adipates,dibutoxyethoxyethyl adipate, diisobutyl adipate, sebacic esters, azelaicesters, citric esters, and tartaric esters; and fatty acid esters suchas, for example, glycerol, mono- di- or triacetate, and sodium diethylsulfosuccinate; and any analogs, derivatives, copolymers andcombinations thereof.

In other embodiments, the plasticizers include, but are not limited toethers and polyethers such as, for example, poly(alkylene glycols) suchas poly(ethylene glycols) (PEG), polypropylene glycols), andpoly(ethylene/propylene glycols); PEG derivatives such as, for example,methoxy poly(ethylene glycol) (mPEG); and ester-ethers such as, forexample, diethylene glycol dibenzoate, dipropylene glycol dibenzoate,and triethylene glycol caprate-caprylate; and any analogs, derivatives,copolymers and combinations thereof.

The term “low molecular weight polymers” refers to agents that can becombined with a water-containing solvent or a lipid-containing solventat temperatures that range from about room temperature to about the bodytemperature of subject to form a liquid or semi-solid. In someembodiments, such a low molecular weight polymeric material can be anypolymer that can dissolve in a limited amount of water and leach from apolymeric material. In other embodiments, such a low molecular weightpolymeric material can be any polymer that can dissolve in a bodilyfluid. The molecular weight of such a polymer will vary, and thestructure of the polymer will guide one skilled in the art in thedetermination of the appropriate molecular weight to use in a particularapplication.

In other embodiments, the plasticizers include, but are not limited to,amides such as, for example, oleic amide, erucic amide, and palmiticamide; alkyl acetamides such as, for example, dimethyl acetamide;sulfoxides such as for example, dimethyl sulfoxide; pyrrolidones suchas, for example, n-methylpyrrolidone; sulfones such as, for example,tetramethylene sulfone; acids such as, for example, oxa monoacids, oxadiacids such as 3,6,9-trioxaundecanedioic acid, polyoxa diacids, ethylester of acetylated citric acid, butyl ester of acetylated citric acid,capryl ester of acetylated citric acid, and diglycolic acids such asdimethylol propionic acid; and any analogs, derivatives, copolymers andcombinations thereof.

In other embodiments, the plasticizers include, but are not limited tovegetable oils including, but not limited to, epoxidized soybean oil;linseed oil; castor oil; coconut oil; fractionated coconut oil;epoxidized tallates; and esters of fatty acids such as stearic, oleic,myristic, palmitic, and sebacic acid; essential oils including, but notlimited to, angelica oil, anise oil, arnica oil, aurantii aetheroleum,valerian oil, basilici aetheroleum, bergamot oil, savory oil, buccoaetheroleum, camphor, cardamomi aetheroleum, cassia oil, chenopodiumoil, chrysanthemum oil, cinae aetheroleum, citronella oil, lemon oil,citrus oil, costus oil, curcuma oil, carlina oil, elemi oil, tarragonoil, eucalyptus oil, fennel oil, pine needle oil, pine oil, filicis,aetheroleum, galbanum oil, gaultheriae aetheroleum, geranium oil, guaiacwood oil, hazelwort oil, iris oil, hypericum oil, calamus oil, camomileoil, fir needle oil, garlic oil, coriander oil, carraway oil, lauriaetheroleum, lavender oil, lemon grass oil, lovage oil, bay oil, lupulistrobuli aetheroleum, mace oil, marjoram oil, mandarine oil, melissaoil, menthol, millefolii aetheroleum, mint oil, clary oil, nutmeg oil,spikenard oil, clove oil, neroli oil, niaouli, olibanum oil, ononidisaetheroleum, opopranax oil, orange oil, oregano oil, orthosiphon oil,patchouli oil, parsley oil, petit-grain oil, peppermint oil, tansy oil,rosewood oil, rose oil, rosemary oil, rue oil, sabinae aetheroleum,saffron oil, sage oil, sandalwood oil, sassafras oil, celery oil,mustard oil, serphylli aetheroleum, immortelle oil, fir oil, teatreeoil, terpentine oil, thyme oil, juniper oil, frankincense oil, hyssopoil, cedar wood oil, cinnamon oil, and cypress oil; and other oils suchas, for example, fish oil; and, any analogs, derivatives, copolymers andcombinations thereof.

It should be appreciated that, in some embodiments, one of skill in theart may select one or more particular plasticizing agents in order toexclude any one or any combination of the above-described plasticizingagents.

In some embodiments, the plasticizing agent can include a component thatis water-soluble. In other embodiments, the plasticizing agent can bemodified to be water-soluble. In some embodiments, the plasticizingagent can include a component that is lipid-soluble. In otherembodiments, the plasticizing agent can be modified to be lipid-soluble.Any functional group can be added to modify the plasticizer's behaviorin a solvent such as, for example, body fluids that are present in vivo.

In other embodiments, the functional groups can include, but are notlimited to, oxygen-containing groups such as, for example, alcohols,ethers, phenols, and derivatives thereof. Such oxygen-containing groupsinclude, but are not limited to, acetonides, alcohols, alkoxides,bisphenols, carbinols, cresols, diols, enols, enolates, epoxides,ethers, glycols, hydroperoxides, peroxides, phenols, phenolates,phenoxides, pinacols, trioxides, and ynols.

In other embodiments, the functional groups can include, but are notlimited to, oxygen-containing groups such as, for example, aldehydes,ketones, quinones and derivatives thereof. Such oxygen-containing groupsinclude, but are not limited to, acetals, acyloins, aldehydes, carbonylcompounds, diosphenols, dypnones, hemiacetals, hemiketals, ketals,ketenes, keto compounds, ketones, quinhydrones, quinomethanes, quinines,and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, oxygen-containing groups such as, for example, carboxylicacids and derivatives thereof. Such oxygen-containing groups include,but are not limited to, carboxylic acids, oxoacids, sulfonic acids, acidanhydrides, acid thioanhydrides, acyl groups, acyl halides, acylals,anhydrides, carboxylic acids, cyclic acid anhydrides, cyclic anhydrides,esters, fulgides, lactides, lactols, lactones, macrolides, naphthenicacids, ortho acids, ortho esters, oxo carboxylic acids, peroxy acids,and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, nitrogen-containing groups containing one nitrogen such as,for example, aldimines, aldoximes, alkoxyamines, amic acids, amides,amines, amine oxides, amine ylides, carbamates, hemiaminals,carbonitriles, carboxamides, isocyanides, cyanates, isocyanates,diisocyanates, cyanides, cyanohydrins, diacylamines, enamines,fulminates, hemiaminals, hydroxamic acids, hydroximic acids,hydroxylamines, imides, imidic acids, imidines, imines, oximes,isoureas, ketenimines, ketimines, ketoximes, lactams, lactims, nitriles,nitro, nitroso, nitrosolic acids, oxime O-ethers, quaternary ammoniumcompounds, quinone imines, quinonoximes, azomethines, ureides,urethanes, and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, nitrogen-containing groups containing two or more nitrogenssuch as, for example, aldazines, amide hydrazones, amide oximes,amidines, amidrazones, aminals, amine imides, amine imines, isodiazenes,azans, azides, azo imides, azines, azo compounds, azomethine imides,azoxy compounds, carbodiimides, carboxamidines, diamidides, diazocompounds, diazoamino compounds, diazoates, diazooxides, formamidinedisulfides, formazans, hydrazides, hydrazide hydrazones, hydrazideimides, hydrazidines, hydrazines, hydrazo compounds, hydrazones,ketazines, nitramines, nitrile imines, nitrimines, nitrolic acids,nitrosamides, nitrosamines, nitrosimines, ortho amides, semicarbazones,semioxamazones, triazanes, triazenes, and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, sulfur-containing groups such as thio, thiol, thioether,sulfonyl, sulfido, sulfinamides, sulfilimines, sulfimines, sulfimides,sulfinamidines, sulfines, sulfinic acids, sulfinic anhydrides,sulfinylamines, sulfonamides, sulfones, sulfonediimines, sulfonic acids,sulfonic anhydrides, sulfoxides, sulfoximides, and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, silyl groups; halogens; selenoethers; trifluoromethyls;thio-derivatives of urethanes where at least one oxygen atom is replacedby a sulfur atom; phosphoryls, phosphonates, and phosphinates; andethyleneically unsaturated groups such as, for example, allyl, acryloyl,methacrylol, maleate and maleimido; and combinations thereof.

In other embodiments, the functional group may include light scatteringgroups, magnetic groups, nanogold, other proteins, a solid matrix,radiolabels, carbohydrates, and combinations thereof.

The molecular weights of the plasticizers can range from about 10Daltons to about 100,000 Daltons; from about 25 Daltons to about 50,000Daltons; from about 50 Daltons to about 25,000 Daltons; from about 100Daltons to about 10,000 Daltons; from about 200 Daltons to about 7,500Daltons; from about 500 Daltons to about 5000 Daltons; from about 10Daltons to about 5000 Daltons; from about 10 Daltons to about 2500Daltons; from about 10 Daltons to about 2000 Daltons; from about 10Daltons to about 1750 Daltons; from about 10 Daltons to about 1500Daltons; from about 10 Daltons to about 1000 Daltons; from about 10Daltons to about 500 Daltons; under 500 Daltons; and any range therein.In some embodiments, the PEGs have a molecular weight of less than about1500 Daltons. In other embodiments, the PEGs have a molecular weightranging from about 400 Daltons to about 600 Daltons and can be obtainedby using a mixture of PEGs such as, for example, about a 50/50 mixtureof PEG 400 and PEG 800.

In some embodiments, the use of the plasticizing agents of the presentinvention can increase the strain-to-failure of a material by a factorranging from about 1.01 to about 100; from about 1.03 to about 100; fromabout 1.05 to about 100; from about 1.05 to about 50; from about 1.05 toabout 30; from about 1.05 to about 25; from about 1.1 to about 20; fromabout 1.25 to about 20; from about 1.5 to about 20; from about 1.75 toabout 20; from about 2 to about 10; from about 2 to about 5; or anyrange therein.

Concentrations of Agents

The agents of the present invention can have properties that arebiobeneficial, bioactive, diagnostic, ameliorative, plasticizing or acombination thereof. For example, classification of an agent as abiobeneficial agent does not preclude the use of that agent as abioactive agent, diagnostic agent and/or plasticizing agent. Likewise,classification of an agent as a bioactive agent does not preclude theuse of that agent as a diagnostic agent, biobeneficial agent and/orplasticizing agent. Furthermore, classification of an agent as aplasticizing agent does not preclude the use of that agent as abiobeneficial agent, bioactive agent, and/or diagnostic agent. Moreover,each agent may also have an ability to ameliorate a symptom of adisease.

It should be appreciated that the plasticizers can be blended, mixed,bonded, or otherwise combined with other active agents to obtain otherdesired functions such as, for example, an added therapeutic,prophylactic, ameliorative and/or diagnostic function. In someembodiments, the plasticizers can be linked to the polymeric compositionor other agents through ether, amide, ester, orthoester, anhydride,ketal, acetal, and all-aromatic carbonate linkages. In theseembodiments, an agent such as a plasticizing agent can be designed tohydrolyze in vivo and leach from the polymeric composition at apredetermined rate.

Accordingly, the amounts of the agents that are added to the polymericcompositions can vary according to a variety of factors including, butnot limited to, the biological activity of the agent; the age, bodyweight, response, and the past medical history of the subject; and, thepharmacokinetic and pharmacodynamic effects of the agents or combinationof agents. Factors such as these are routinely considered by one ofskill in the art. Effective amounts, for example, may be extrapolatedfrom in vitro and/or animal model systems. In some embodiments, theagent or combination of agents have a concentration that ranges fromabout 0.01% to about 75%; from about 0.05% to about 70%; from about 0.1%to about 60%; from about 0.25% to about 60%; from about 0.5% to about50%; from about 0.75% to about 40%; from about 1.0% to about 30%; fromabout 2% to about 20%; and, any range therein, where the percentage isbased on the total weight of the polymer and agent or combination ofagents.

Agents can be combined to obtain a combination of desired properties andfunctions in a polymeric material. In some embodiments, a secondaryplasticizer can be combined with a primary plasticizer in an amount thatranges from about 0.01% to about 50%; from about 0.05% to about 50%;from about 0.75% to about 50%; from about 1.0% to about 40%; from about2% to about 30%; from about 1% to about 20%; from about 3% to about 20%;from about 3% to about 10%; or any range therein, as a weight percentagebased on the total weight of the plasticizer. In other embodiments, oneor more plasticizers may leach from a medical article, and one or moreplasticizers may remain, while providing a polymeric material withsufficient rigidity.

Forming a Medical Article

The plasticizing agent can be localized in an implant during a processof forming the implant, and the localization of plasticizer can bebeneficial for a variety of reasons such as, for example, use of lessplasticizer in select regions; use of a preferred plasticizer in selectregions such as, for example, a plasticizer with a lower toxicity orfaster leaching rate; modification of mechanical properties of selectregions of an implant; leaching of less plasticizer for elimination by asubject; and combinations thereof. In some embodiments, there may be noplasticizer in the regions outside of the high-strain regions in animplant. In other embodiments, there may be less plasticizer in theregions outside of the high-strain regions in an implant. In embodimentswhere less plasticizer is desired in the regions outside of thehigh-strain regions, the amount of plasticizer in the regions outside ofthe high-strain regions can have 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95%, or any range therein, less plasticizer than thehigh-strain regions.

Processes for forming a medical article include, but are not limited to,casting, molding, coating, and combinations thereof. In someembodiments, the implant is formed in a casting process, and themechanical properties of the high-strain regions of the implant arecontrolled by concentrating the plasticizer in the high-strain regions,by using different plasticizers in the high-strain regions, by usingplasticizer only in the high-strain regions, or a combination thereof.Casting an implant involves pouring a liquid polymeric composition intoa mold. In one embodiment, the localization of plasticizer in an implantduring such casting can be obtained by varying the amount and/or type ofplasticizer in the polymeric composition during pouring as desired suchthat the plasticizer becomes localized in the formed implant.

In other embodiments, the implant is formed in a molding process, whichincludes, but is not limited to, compression molding, extrusion molding,injection molding, and foam molding. The mechanical properties of thehigh-strain regions of the implant are controlled by concentrating theplasticizer in the high-strain regions, by using different plasticizersin the high-strain regions, by using plasticizer only in the high-strainregions, or a combination thereof.

In compression molding, solid polymeric materials are added to a moldand pressure and heat are applied until the polymeric material conformsto the mold. The solid form may require additional processing to obtainthe final product in a desired form. The solid polymeric materials canbe in the form of particles that can vary in mean diameter from about 1nm to about 1 cm, from about 1 nm to about 10 mm, from about 1 nm toabout 1 mm, from about 1 nm to about 100 nm, or any range therein. Inone embodiment, the localization of plasticizer in an implant duringsuch compression molding can be obtained by varying the amount and/ortype of plasticizer in the solid polymeric materials while adding thesolid polymeric materials to the mold as desired such that theplasticizer becomes localized in the formed implant.

In extrusion molding, solid polymeric materials are added to acontinuous melt that is forced through a die and cooled to a solid form.The solid form may require additional processing to obtain the finalproduct in a desired form. The solid polymeric materials can be in theform of particles that can vary in mean diameter from about 1 nm toabout 1 cm, from about 1 nm to about 10 mm, from about 1 nm to about 1mm, from about 1 nm to about 100 nm, or any range therein. In oneembodiment, the localization of plasticizer in an implant during suchextrusion molding can be obtained by varying the amount and/or type ofplasticizer in the solid polymeric materials while adding the solidpolymeric materials to the extrusion mold as desired such that theplasticizer becomes localized in the formed implant.

In injection molding, solid polymeric materials are added to a heatedcylinder, softened and forced into a mold under pressure to create asolid form. The solid form may require additional processing to obtainthe final product in a desired form. The solid polymeric materials canbe in the form of particles that can vary in mean diameter from about 1nm to about 1 cm, from about 1 nm to about 10 mm, from about 1 nm toabout 1 mm, from about 1 nm to about 100 nm, or any range therein. Inone embodiment, the localization of plasticizer in an implant duringsuch injection molding can be obtained by varying the amount and/or typeof plasticizer in the solid polymeric materials while adding the solidpolymeric materials to the injection mold as desired such that theplasticizer becomes localized in the formed implant.

In foam molding, blowing agents are used to expand and mold solidpolymeric materials into a desired form, and the solid polymericmaterials can be expanded to a volume ranging from about two to about 50times their original volume. The polymeric material can be pre-expandedusing steam and air and then formed in a mold with additional steam; ormixed with a gas to form a polymer/gas mixture that is forced into amold of lower pressure. The solid form may require additional processingto obtain the final product in a desired form. The solid polymericmaterials can be in the form of particles that can vary in mean diameterfrom about 1 nm to about 1 cm, from about 1 nm to about 10 mm, fromabout 1 nm to about 1 mm, from about 1 nm to about 100 nm, or any rangetherein. In one embodiment, the localization of plasticizer in animplant during such foam molding can be obtained by varying the amountand/or type of plasticizer in the solid polymeric materials while addingthe solid polymeric materials to the foam mold as desired such that theplasticizer becomes localized in the formed implant.

In other embodiments, a stent is formed by injection molding orextrusion of a tube followed by cutting a pattern of a stent into thetube. In these embodiments, a mixture of polymer and plasticizer can beadded prior to injection molding or extrusion or, in the alternative,the plasticizer can be absorbed by the stent after the stent has beenformed.

In other embodiments, a polymeric coating comprising a plasticizingagent can be applied to a body of a medical article, wherein the body ofthe medical article can be polymeric or metal. In these embodiments, themedical article can be a stent comprising a metal body that is coatedwith a polymeric material to provide rigidity upon leaching of theplasticizing agent from the polymeric coating. In these embodiments, themedical article can be a stent comprising a polymeric body that iscoated with a polymeric material to provide rigidity upon leaching ofthe plasticizing agent from the polymeric coating. It should beappreciated that any of the foregoing agents can be mixed, blended orotherwise connected with a medical device or a coating for a medicaldevice. By way of example, a stent or a coating for a stent can containa polymeric composition comprising paclitaxel, docetaxel, rapamycin oreverolimus that can leach from the polymeric composition in vivo.

Any method of coating can be used in practicing the present inventionincluding, but not limited to, spraying, dipping, brushing, pouring,dripping, spinning, roller coating, meniscus coating, powder coating andvarious inking approaches such as inkjet-type application. In someembodiments, the method of coating is spraying. In other embodiments,the method of coating is dipping. In other embodiments, additionalprocess steps are necessary such as, for example, the application ofheat or energy to medical device and/or coating.

In some embodiments, the plasticizing agent can be localized in animplant by later adding a highly-penetrating plasticizing agent toselect regions of the implant. In some of these embodiments, theplasticizing agent can be any of the plasticizing agents taught above.In other of these embodiments, the plasticizing agent can also be asolvent with some ability to solubilize, and thus enter, a polymericmaterial in the implant. Methods of applying the plasticizing agent caninclude, but are not limited to, the coating methods taught herein.

The solvent may be chosen based on several criteria including, forexample, its polarity, molecular size, biocompatibility, reactivity andpurity. Other physical characteristics of the solvent may also be takeninto account, including the solubility limit of the polymer in thesolvent; oxygen and other gases in the solvent; the viscosity and vaporpressure of the combined solvent and polymer; the ability of the solventto diffuse through an underlying material; and the thermal stability ofthe solvent. One of skill in the art has access to scientific literatureand data regarding the solubility of a wide variety of polymers.Furthermore, one of skill in the art will appreciate that the choice ofsolvent may begin empirically by calculating the Gibb's free energy ofdissolution using available thermodynamic data. Such calculations allowfor a preliminary selection of potential solvents to test in alaboratory. It is recognized that process conditions can affect thechemical structure of the underlying materials and, thus, affect theirsolubility in a solvent. It is also recognized that the kinetics ofdissolution are a factor to consider when selecting a solvent, because aslow dissolution of a material may not affect the performancecharacteristics of a product where the product is produced relativelyquickly.

The solvents can include, but are not limited to, chloroform, dimethylacetamide (DMAC), dimethyl formamide (DMF), tetrahydrofuran (THF),cyclohexanone, xylene, toluene, acetone, water, methanol, ethanol,propanol, i-propanol, methyl ethyl ketone, propylene glycol monomethylether, methyl butyl ketone, ethyl acetate, n-butyl acetate, dioxane andcombinations thereof. Examples of solvent combinations include, but arenot limited to, chloroform and acetone (50/50); DMAC and methanol (50:50w/w); water, i-propanol, and DMAC (10:3:87 w/w); i-propanol and DMAC(80:20, 50:50, or 20:80 w/w); acetone and cyclohexanone (80:20, 50:50,or 20:80 w/w); acetone and xylene (50:50 w/w); acetone, xylene and FLUXREMOVER AMS® (93.7% 3,3-dichloro-1,1,1,2,2-pentafluoropropane and1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance is methanolwith trace amounts of nitromethane; Tech Spray, Inc.) (10:40:50 w/w);and 1,1,2-trichloroethane and chloroform (80:20 w/w). In someembodiments, the solvents can be polar. In these embodiments, the polarsolvents can include acetone, methanol, ethanol, or i-propanol. In otherembodiments, the solvents can be non-polar. In these embodiments, thesolvents can include acetone, chloroform, carbon tetrachloride,tetrachloroethylene, or dichloromethane. In other embodiments, thesolvents can be amphiphilic. In other embodiments, the solvents can bean alkyl halide such as, for example, methylene chloride or ethylenedichloride. In other embodiments, the solvents can be rated as Class 3solvents according to the ICH Guidelines (Guidance for Industry, Q3CImpurities: Residual Solvents, CDER, Rockville, Md. 20857). In otherembodiments, the solvents can be rated as Class 2 solvents according tothe ICH Guidelines. See Id. In other embodiments, the solvents can berated as Class 1 solvents according to the ICH Guidelines. See Id.

In some embodiments, a pore forming agent can be used to create porosityin a polymeric composition to, for example, aid in the introduction ofplasticizer into a polymeric material and the leaching of plasticizerfrom the polymeric material. Porosity can be introduced in the polymericcompositions by any method known to one of skill in the art. In oneembodiment, the porosity can be introduced into a medical article byadding particles to a polymeric material used to form the medicalarticle and later removing the particles to create a porous structure.Pore size can be controlled by screening the particles according to sizeand adding particles of a predetermined size to the materials. Theparticles may include, but are not limited to, salts and water-solublepolymers.

In some embodiments, water-soluble polymers include, for example,polymeric salts, polyvinyl alcohol, polyethylene glycol, polyethyleneoxide, glucose, dextran, dextrose, lactose, and combinations thereof.Such particles may be removed, for example, by washing in water or avery dilute acid bath. Examples of non-polymeric salts include, but arenot limited to, NaCl and sodium bicarbonate. In other embodiments, themethods of forming the porous structure include stretching the polymericmaterial to its desired dimensions induce formation of pores or voids inthe material. In other embodiments, the methods of forming the porousstructure include precipitation of a cast polymer solution in an aqueousliquid such as, for example, water, prior to curing. In otherembodiments, the methods of forming the porous structure includepressuring and sintering a powder of a polymer to form a structure withinternal bridging that may be stretched to control the size of the porestructure created; and, bombardment of a polymeric material withhigh-energy particles followed by chemical etching to create a porestructure.

In some embodiments, a layer is “porous” when it has a void-to-volumepercentage that ranges from about 40% to about 90%, from about 70% toabout 80%, or any range therein. In some embodiments, a layer is“non-porous” when it has a void-to-volume percentage that ranges fromabout 0% to about 5%, from about 1% to about 3%, and any range therein.The “void-to-volume percentage” is defined as the volume of the poresdivided by the total volume of the layer including the volume of thepores. In some embodiments, the void-to-volume percentage can bemeasured using standard test method BSR/AAMI/ISO 7198, which has beenadopted in-whole as a revision of ANSI/AAMI VP20-1994 (CardiovascularImplants—Vascular Prosthesis section 8.2.1.2, Method for GravimetricDetermination of Porosity, Am. Nat'l Stds. Inst./Assoc. for the Adv. ofMed. Instr.)

In other embodiments, the implant comprises an osmotic pump to enhanceleaching of the plasticizer from a medical article such as, for example,a medical implant. In these embodiments, the osmotic pump can include apolymeric material having an agent and a porous structure that canrelease the agent. Fluid enters the porous material and creates anosmotic pressure that induces release of the agent in vivo. In someembodiments, the osmotic pump can include an osmotic agent such as, forexample, a plasticizing agent in salt form, which acts to imbibe waterfrom the surrounding medium through the porous structure. Pressure isgenerated within a medical article such as, for example, a stent, andforces the plasticizing agent out of the device through the porousstructure.

EXAMPLES Example 1

The strain-to-failure of a specimen of a material can be tested usingTest Procedure ASTM D882. Specimens used in the testing can be 1″×6″strips cut from a thin sheet or film for use in this procedure.

The specimens can be placed in the grips of an Instron Universal Testerand pulled until failure. For the ASTM D882 test procedure, the speed atwhich a specimen is stressed and the separation of the grip device onthe specimen are based on the elongation to break of the material. Theelongation and tensile modulus can be calculated from the displacementof the crossheads of the grip device, or with an extensometer. Since thematerials of the present invention are used in an organ of a livingsubject, the materials should be tested at the temperature present inthe subject. A thermal chamber can be installed on the Instron UniversalTester. The chamber is designed to allow the test mounts from the baseand crosshead of the Instron to pass through the top and bottom of thechamber. Standard test fixtures are installed inside the chamber, andtesting is conducted inside the controlled thermal environment. Thechamber has internal electric heaters for elevated temperatures and usesexternal carbon dioxide gas as a coolant for reduced temperatures.

Example 2

A stent can be formed using standard formation techniques and aplasticizer can then be absorbed by the formed stent. The stent can beformed by first forming a poly(L-lactide) cylindrical tube that isapproximately 1.0 inches in length with an outer diameter ofapproximately 0.053 inches and a wall-thickness of approximately 0.006inches. The tube can be formed by injection molding. The stent patterncan be cut into the tube using an appropriate laser source.

The formed stent can then be dipped into acetone for about 15 seconds toallow the poly(L-lactide) material to absorb some acetone, which canserve as the leachable plasticizer during placement of the stent in asubject.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. One of skill in the art willappreciate that the any of the teachings can be used together or incombination to fulfill the purpose and nature of the invention.

1. A method of producing a medical article comprising a temporaryplasticizing agent, wherein the method comprises combining a polymerwith a plasticizing agent capable of sufficiently increasing astrain-to-failure in the polymeric material to prevent or reduce aformation of cracks in the polymeric material while placing an implantin a subject, wherein the plasticizing agent leaches from the polymericmaterial after placing the implant in the subject to provide asufficient rigidity in the polymeric material, and wherein theplasticizing agent leaches from the polymeric material in less than anamount of time necessary for a required dimension of the implant tochange substantially in response to a stress.
 2. The method of claim 1,wherein the implant comprises a stent or a vena cava filter.
 3. Themethod of claim 2, wherein the stent is selected from a group consistingof vascular stents, renal stents, biliary stents, pulmonary stents andgastrointestinal stents.
 4. The method of claim 1, wherein the implantcomprises a biodegradable polymer.
 5. The method of claim 1, wherein theimplant comprises a polymer selected from a group consisting ofpolyesters, polyhydroxyalkanoates (PHAs), poly(ester amides); aminoacids; poly(ethylene glycol) (PEG) and/or alcohol groups,polycaprolactones, poly(L-lactide), poly(D,L-lactide),poly(D,L-lactide-co-PEG) block copolymers,poly(D,L-lactide-co-trimethylene carbonate), polyglycolides,poly(lactide-co-glycolide), polydioxanones, polyorthoesters,polyanhydrides, poly(glycolic acid-co-trimethylene carbonate),polyphosphoesters, polyphosphoester urethanes, poly(amino acids),polycyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonates), polycarbonates, polyurethanes, copoly(ether-esters),polyalkylene oxalates, polyphosphazenes, PHA-PEG, poly(tyrosinecarbonates), poly(tyrosine arylates), polyanhydrides, poly(hydroxyethylmethacylate), poly(N-acylhydroxyproline)esters, poly(N-palmitoylhydroxyproline)esters, polyphosphazenes, and any derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof. 6.The method of claim 5, wherein the PHA is selected from a groupconsisting of poly(α-hydroxyacids), poly(β-hydroxyacids),poly(3-hydroxybutyrate), poly(3-hydroxybutyrate-co-valerate),poly(3-hydroxypropionate), poly(3-hydroxyhexanoate),poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), orpoly(4-hydroxyhexanoate), poly(hydroxyvalerate), and any derivatives,analogs, homologues, congeners, salts, copolymers and combinationsthereof.
 7. The method of claim 1, wherein the plasticizing agent isdiagnostic, bioactive, biobenefical, or a combination thereof.
 8. Themethod of claim 1, wherein the plasticizing agent comprises a componentthat is water-soluble.
 9. The method of claim 1, wherein theplasticizing agent comprises a component that is lipid-soluble.
 10. Themethod of claim 1, wherein the plasticizing agent comprises a componentthat is biodegradable.
 11. The method of claim 1, wherein theplasticizing agent comprises a component selected from a groupconsisting of low molecular weight polymers, copolymers and oligomers;small organic molecules; lactic acid oligomers; dimers of cyclic lacticacid and glycolic acid; hydrogen bond forming organic compounds;polyols; alkanols; sugar alcohols and anhydrides of sugar alcohols;polyethers; esters; polyesters; aliphatic acids; saturated andunsaturated fatty acids; fatty acid esters; fatty alcohols; cholesterol;steroids; phospholipids; proteins; oils; silicones; acetylatedmonoglycerides; diglycerides; triglycerides; amides; acetamides;sulfoxides; sulfones; pyrrolidones; oxa acids; diglycolic acids; and anyderivatives, analogs, homologues, congeners, copolymers and combinationsthereof.
 12. The method of claim 1, wherein the plasticizing agentcomprises a component selected from a group consisting of lactic acid;dimers of cyclic lactic acid and glycolic acid; poly(ethylene glycol),poly(propylene glycol), poly(vinyl pyrrolidone), phosphorylcholine,glycosaminoglycans, phospholipids, carboxymethylcellulose, hyaluronicacid, heparin, hirudin, poly(acrylamide methyl propane sulfonic acid),poly(styrene sulfonate), sulfonated dextran, dermatan sulfate, RGD,collagen, chitin, chitosan, elastin and any derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof. 13.The method of claim 12, wherein the poly(ethylene glycol) has amolecular weight of less than 1500 Daltons.
 14. The method of claim 1,wherein the plasticizing agent comprises a component selected from agroup consisting of castor oil, fish oil, garlic oil, ethanol, xylene,dimethyl formamide, dimethyl sulfoxide, propylene glycol, glycerol,lecithin, and derivatives and combinations thereof.
 15. The method ofclaim 1, wherein the plasticizing agent is localized in high-strainareas of the implant.
 16. The method of claim 1, wherein theplasticizing agent leaches sufficiently from the implant in a subject inless than an amount of time required for a change in a requireddimension of the implant in an amount ranging from about 0.1% to about50%.
 17. The method of claim 1, wherein the implant comprises a stent ora vena cava filter, the required dimension is a diameter of the stent orvena cava filter following deployment of the stent or vena cava filterin a subject, and the change is a reduction in the diameter of the stentor vena cava filter ranging from about 0.1% to about 20%.
 18. The methodof claim 1, wherein the implant comprises pores that were createdthrough the use of a pore forming agent.
 19. The method of claim 1,wherein the implant comprises an osmotic pump to enhance leaching of theplasticizer from the implant.